Roles of Gut Microbiota in the Regulation of Hippocampal Plasticity, Inflammation, and Hippocampus-Dependent Behaviors

The study of the gut microbiota-brain axis has become an intriguing field, attracting attention from both gastroenterologists and neurobiologists. The hippocampus is the center of learning and memory, and plays a pivotal role in neurodegenerative diseases, such as Alzheimer’s disease (AD). Previous studies using diet administration, antibiotics, probiotics, prebiotics, germ-free mice, and fecal analysis of normal and specific pathogen-free animals have shown that the structure and function of the hippocampus are affected by the gut microbiota. Furthermore, hippocampal pathologies in AD are positively correlated with changes in specific microbiota. Genomic and neurochemical analyses revealed significant alterations in genes and amino acids in the hippocampus of AD subjects following a remarkable shift in the gut microbiota. In a recent study, when young animals were transplanted with fecal microbiota derived from AD patients, the recipients showed significant impairment of cognitive behaviors, AD pathologies, and changes in neuronal plasticity and cytokines. Other studies have demonstrated the side effects of antibiotic administration along with the beneficial effects of probiotics, prebiotics, and specific diets on the composition of the gut microbiota and hippocampal functions, but these have been mostly preliminary with unclear mechanisms. Since some specific gut bacteria are positively or negatively correlated to the structure and function of the hippocampus, it is expected that specific gut bacteria administration and other microbiota-based interventions could be potentially applied to prevent or treat hippocampus-based memory impairment and neuropsychiatric disorders such as AD.


INTRODUCTION
The human microbiome is established early in life, and consists of approximately 3.8 × 10 13 symbiotic microorganisms (Lukiw, 2016;O'Hagan et al., 2017). In the gastrointestinal tract, the colonized gut microbiota is a complex and dynamic community of microorganisms that can communicate with the host to influence the brain and behavior (Liang et al., 2015;Hu et al., 2020). Under normal conditions, aging is associated with changes in higher brain functions such as learning and memory, as well as dysbiosis in the gut microbiome (Daulatzai, 2014;Distrutti et al., 2014). One hundred years ago, the Nobel Prize winner Elie Metchnikoff proposed that cognitive decline and senility might be delayed by manipulating the intestinal microbiome with hostfriendly bacteria (Scott et al., 2017). However, no significant progress showing that the bacterial constituents of the gut microbiota can influence brain function has been made over the past decade (O'Hagan et al., 2017). The term gut-microbiota-brain axis or gut-brain-axis is used to describe the relationship between the gut and the brain (Bienenstock and Collins, 2010).
The hippocampus, consisting of the cornu ammonis (CA) 1, CA2, CA3, dentate gyrus (DG), and subiculum, is the center of learning and memory (Lisman et al., 2017;Hainmueller and Bartos, 2018). Interestingly, although engrams (memory traces) in CA1 and CA2 do not stabilize over time, reactivation of engrams in the DG can induce recall of artificial memories even after weeks (Hainmueller and Bartos, 2018). Moreover, the hippocampus has also been implicated in depression and anxiety, and hippocampal neurogenesis has been implicated in cognitive processes (Toda et al., 2018). Since the gut microbiota has been shown to play a role in the pathology of Alzheimer's disease (AD) and other memory disorders, we reviewed the current progress on the gut microbiota's influence on the structure and function of the hippocampus and hippocampus-based learning and memory.

IMBALANCED GUT MICROBIOTA IN ALZHEIMER'S DISEASE SUBJECTS AND MODEL ANIMALS
AD is the most common neurodegenerative disorder, ultimately resulting in dementia, and the hippocampus is one of the affected brain regions (Moodley and Chan, 2014). Several clues from human fecal studies have shown that gut microbiota composition is different between AD patients and healthy controls (HCs). For example, AD patients showed lower abundance of Eubacterium but higher abundance of Escherichia/Shigella (Cattaneo et al., 2017), along with obvious changes in Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales (Zhuang et al., 2018). Other studies showed that among AD patients, patients with amnestic mild cognitive impairment, and HCs, the fecal microbial diversity was changed, showing a reduced proportion of phylum Firmicutes but enriched Proteobacteria. These results indicated that distinct microbial communities, especially enriched Enterobacteriaceae, were associated with AD (Zhuang et al., 2018;Liu et al., 2019). Furthermore, genetargeted analysis of human gut microbiota in AD fecal samples found some unique gut bacterial sequences that were rarely seen in controls, highlighting the significant difference in the gut microbial genotypes between the AD patients and healthy human populations (Paley et al., 2018).
AD model rodents have been frequently used to explore alterations in the gut microbiota in AD. In the feces of AD mice, the microbiota composition and diversity were changed, with shortchain fatty acid composition  and the amount of trypsin reduced when compared to wild type (WT) mice (Brandscheid et al., 2017). Additionally, the composition and diversity of the gut microbiota changed greatly with aging and AD pathology. Impaired spatial memory appeared in 6-month-old APP/PS1 AD model mice and was further aggravated in the 8month-old mice. This was consistent with the accumulation in amyloid plaque and the remarkable shift in gut microbiota compared to WT mice. The abundance of Helicobacteraceae, Desulfovibrionaceae, Odoribacter, and Helicobacter increased significantly, while that of Prevotella decreased significantly (Shen et al., 2017). At 3 months of age, the fecal bacterial profiles did not show significant differences between the AD mice and control mice; however, at 6 months, the abundance of Turicibacteriaceae and Rikenellaceae increased in both groups, and an increase in Proteobacteria abundance was seen in AD mice after 6 months, particularly that of the genus Sutterella (Betaproteobacteria); the inflammation-related family Erysipelotrichaceae was more abundant in 24-month-old AD mice than in WT mice (Bauerl et al., 2018). These results indicated that AD pathology shifted gut microbiota composition towards an inflammation-related bacterial profile during aging, and suggested that these changes could contribute to disease progression and severity (Bauerl et al., 2018). Importantly, recent studies showed that when the gut microbiota from AD patients was transplanted into AD mice, the recipient mice showed more severe cognitive impairment and activated microglia in the hippocampus, and these effects could be effectively inhibited by transplantation of healthy human gut microbiota .
Thus, in both AD patients and AD model animals, significant changes in the gut microbiota have been reported, some of which increased while others decreased ( Figure 1 and Table 1), indicating that manipulation of the gut microbiota may be a promising intervention for the prevention or treatment of AD.

HIPPOCAMPAL NEUROCHEMICALS AND NEUROPLASTICITY ARE REGULATED BY THE GUT MICROBIOTA
Changes in neurochemicals form the basis of structural and functional plasticity of the hippocampus. An early analysis of the cerebral metabolome revealed that the concentrations of 38 metabolites differed significantly between germ-free (GF) mice and WT mice, indicating that intestinal microbiota is closely related to brain health and disease and its functions, such as development, learning, memory, and behavior (Matsumoto et al., 2013). Kawase et al. reported that compared to specific pathogenfree (SPF) mice, hippocampal amino acids and neurochemicals in GF mice at postnatal week 7 were significantly changed, showing lower concentrations of L-Ala, L-Arg, L-Gln, L-Ile, L-Leu, L-Phe, L-Val, and GABA, but higher concentrations of Ser (Kawase et al., 2017). Another study showed that GF mice showed higher hippocampal levels of creatine, N-acetyl-aspartate, lactate, and taurine but lower levels of succinate than SPF mice (Swann et al., 2017). Furthermore, the hippocampus of GF mice showed an increase in synapse-promoting genes and markers of reactive microglia and synaptic density, all of which could be reversed by colonization with human Bifidobacterium species or conventional murine microbiota, indicating that Bifidobacteria are involved in the establishment of functional neural circuits in the hippocampus (Luck et al., 2020). Interestingly, one hippocampal microRNA (miRNA) study using GF, conventional, and GF colonized mice showed an increase in miR-294-5p expression in GF animals but normalized expression following colonization, indicating that the gut microbiota plays an important role in modulating small RNAs that influence hippocampal gene expression . Similarly, one study showed that in the hippocampus of GF mice, 1355 lncRNAs were upregulated and 875 lncRNAs were downregulated. Further analysis revealed that most of their target genes were highly associated with cardiac hypertrophy, nuclear factors of activated T cells, gonadotropin-releasing hormone, FIGURE 1 | Altered gut microbiota in AD patients and model mice. Some differences have been noticed regarding the changes of gut microbiota in AD patients or mouse models. For example, Bacteroidetes and Firmicutes decreased (left) at Phylum level while Actinobacteria, Betaproteobacteria, and Proteobacteria increased (right). calcium, and cAMP-response element-binding protein (CREB) signaling pathways (Zhou et al., 2020). The brain-derived neurotrophic factor (BDNF) regulates activity-dependent synaptic plasticity and psychiatric disorders (Bjorkholm and Monteggia, 2016;Leal et al., 2017), while CREB regulates genes related to neuronal differentiation, synaptic plasticity, learning, and memory (Sharma et al., 2019). Studies have shown that both hippocampal BDNF and CREB are regulated by the gut microbiota. The anticancer flavonoid quercetin, a secondary plant metabolite, has been shown to increase gut microbial diversity and relative abundance of Glutamicibacter, Facklamia, and Aerocorrus; increase hippocampal BDNF; and improve learning and memory . Zeng et al. used microarray analysis and revealed that the absence of the gut microbiota from birth was associated with decreased hippocampal CREB but an increase in phosphorylated CREB (pCREB), which could be restored by microbiota colonization in adolescence; hippocampal pCREB expression could be reduced by removal of the gut microbiota from SPF mice using antibiotics (Zeng et al., 2016). Additionally, oral administration of Lactobacillus johnsonii CJLJ103, a member of the human gut microbiota, may alleviate cholinergic memory impairment by increasing BDNF expression and pCREB in the hippocampi . Interestingly, gut microbiotainduced hippocampal BDNF expression might be mediated by the vagus nerve, since it could be regulated by subdiaphragmatic vagotomy (O'Leary et al., 2018). A recent study showed that when fecal microbiota transplantation (FMT) was conducted on aged and young rats, the young rats showed impairment in cognitive behavior, a decrease in dendritic spines and expression of BDNF, N-methyl-D-aspartate receptor NR1 subunit, and synaptophysin, but an increase in the expression of advanced glycation end products (AGEs) and receptors for AGEs. At the phylum level, FMT decreased the relative abundance of Bacteroidetes, while increasing the relative abundance of Actinobacteria. At the genus level, FMT rats showed lower levels of Prevotella, Bacteroides, Parabacteroides, and higher levels of Sutterella .
Furthermore, studies have shown that the morphology and neurogenesis of the hippocampus are regulated by the gut microbiota. Convincing evidence comes from studies of GF animals. Luczynski et al. reported that compared to the control mice, GF mice showed significant hippocampal expansion with shorter pyramidal neurons, and less-branched, stubby mushroom-spines and granule cells (Luczynski et al., 2016). Indirectly, Val-Laillet et al. found that a Western diet (fat 33%, refined carbohydrate 49%) induced a decrease in microbiota activity and hippocampal neurogenesis but increased cell proliferation, higher working memory and reference memory scores, accompanied by a smaller hippocampal granular cell layer volume (Val-Laillet et al., 2017) Similarly, Möhle et al. found that antibiotics, which could severely deplete the intestinal microbiota, significantly decreased hippocampal neurogenesis (Mohle et al., 2016).
Probiotics, diets, and obesity also play roles in the regulation of the hippocampus, which might be mediated by the gut microbiota. Distrutti et al. reported that treatment of aged rats with VSL#3, a probiotic mixture comprising eight gram-positive bacterial strains, increased the abundance of Actinobacteria and Bacteroidetes and modulated the expression of CD11b (a marker for microglia), BDNF, syntaxin, and drebrin in the hippocampus (Distrutti et al., 2014). VSL#3 has also been shown to prevent diet-induced microbiota deficits by increasing the abundance of some taxa such as Streptococcus, Lactobacillus, and Butyrivibrio, which were decreased by the cafeteria (Caf) diet. Meanwhile, hippocampal-dependent place tasks were also regulated by these treatments (Beilharz et al., 2018). However, in the hippocampus, the Caf diet increased the expression of many neuroplastic genes and serotonin receptor 5-HT1A, which are the best predictors of place memory, and are related to the microbiota principal component (PC) 1 (Beilharz et al., 2018). For obese humans, hierarchical clustering with magnetic resonance imaging analysis revealed a specific gut microbiota-brain map profile, and the Shannon index was linked to R2* and fractional anisotropy of the hippocampus (Fernandez-Real et al., 2015). Moreover, changes in waist circumference in obese humans are associated with iron deposition in the hippocampus, and these changes are linked to shifts in the gut microbiome (Blasco et al., 2017).
Taken together, the current findings suggest that the gut microbiota can be regulated by antibiotics, probiotics, diets, and obesity. They further affect hippocampus-dependent behaviors by acting on neurochemicals, neurotrophic factors, transcriptional factors, neurogenesis, and plasticity of pyramidal and granular cells. These findings are summarized in Figure 2 and Table 2.

ALTERATIONS IN THE GUT MICROBIOTA AFFECT HIPPOCAMPUS-DEPENDENT LEARNING AND MEMORY
Numerous studies have revealed that the gut microbiota may affect hippocampus-dependent learning, memory, and behavior. Probiotics regulate learning and memory through action on the gut microbiota. When old (15-17 months) mice were treated with a multi-species live Lactobacillus and Bifidobacteria mixture (Lactobacillus acidophilus CUL60, L. acidophilus CUL21, Bifidobacterium bifidum CUL20, and B. lactis CUL34), the spatial navigation, as shown by the results of a water maze, was moderately improved and the long-term object recognition memory was dramatically improved (O'Hagan et al., 2017). These results indicate that chronic dietary supplements with multi-species live microorganisms have beneficial effects on memory. Kobayashi et al. showed that oral administration of Bifidobacterium breve strain A1 (B. breve A1) to AD mice reversed the impaired behavior in a Y-maze test and the reduced latency in a passive avoidance test. Further gene profiling analysis revealed that B. breve A1 administration suppressed the expression of hippocampal inflammation and immune-reactive genes that were induced by amyloid beta (Ab) (Kobayashi et al., 2017). Additionally, in a mouse model of vascular dementia, Clostridium butyricum treatment was shown to increase the diversity of intestinal bacteria, improve spatial learning and memory dysfunction, and morphological changes in hippocampal granule cells. It also activated the BDNF-PI3K/ Akt pathway in the hippocampus (Liu et al., 2015).
Plant extracts may affect learning and memory through action on the gut microbiota. In a d-galactose-induced aging mouse model, tuna oil administration restored the diversity of the gut microbiota, showing significant changes in 27 key operational taxonomic units; it also alleviated aging and memory deterioration FIGURE 2 | Associations between gut microbiota and the hippocampus-dependent plasticity and behaviors. GF, Germ free; LJ, Lactobacillus johnsonii CJLJ103; VSL3#, a probiotic mixture comprising 8 Gram-positive bacterial strains; caf, cafeteria; LTP, long-term potentiation, the cellular mechanism of synaptic plasticity; TTK, Tetragonia tetragonioides Kuntze extract; R2*, a validated magnetic resonance imaging (MRI) marker of brain iron content which can be rapidly measured under clinical conditions. The taxonomic group of bacteria: Phylum, Class, Order, Family, Genus, Species, were marked with p, c, o, f, g, s. and changed the expression of proteins related to synaptic repair and signal transduction . Additionally, treatment of LW-AFC, an herbal medicine prepared from the traditional Chinese medicine LiuweiDihuang decoction, was given to senescence-accelerated mouse prone 8 (SAMP8) mice, which resulted in improvement of cognitive impairments including spatial learning and memory, active avoidance response, and object recognition memory capability. This was accompanied by significant changes in operational taxonomic units (OTUs; eight increased and 12 decreased) in the gut microbiota. Further examinations showed that there were seven OTUs significantly correlated with all three types of cognitive abilities (three negative and four positive correlations) at the order level, including Bacteroidales, Clostridiales, Desulfovibrionales, and CW040 . Tetragonia tetragonioides Kuntze (TTK) extract was also shown to protect against short-term and special memory loss, which might involve the upregulation of the hippocampal pCREB/pAk/pGSK-3b pathway, expression of BDNF and CNTF, and cytokines such as TNF-a and IL-1b. These changes were accompanied by a decrease in Clostridiales, Erysipelotrichales, and Desulfovibrionales but an increase in Lactobacillales and Bacteroidales (Kim et al., 2020). Such cognition-improving effects were seen in Tibetan fermented milk-treated APP/PS1 AD mice, which showed an increase in intestinal microbial diversity and increased abundance of Bacteroides, Faecalibacterium spp. Mucispirillum, and Ruminiclostridium; cognitive function was negatively correlated with Mucispirillum abundance and positively correlated with Muribaculum and Erysipelatoclostridium abundance (Liu et al., 2020). These results are summarized in Table 3.

GUT MICROBIOTA AND HIPPOCAMPAL INFLAMMATION
Inflammation in the hippocampus is key to the vulnerability and recovery from psychiatric disorders. Several studies have reported that the gut microbiota may change the hippocampal inflammatory response and the related behaviors. For example, in obese mice, alterations in the gut microbiota could be ameliorated by B. pseudocatenulatum CECT 7765 accompanied by reduced Toll-like receptor 2 (TLR2) protein or gene expression in the hippocampus (Agusti et al., 2018). An early study showed that exposure to magnesium deficient diet induced changes in gut microbiota composition that was positively correlated to the levels of hippocampal interleukin-6 (IL-6) (Winther et al., 2015). Beilharz et al. found that a diet with saturated fatty acid and sugar but lacking polyunsaturated fatty acid significantly impaired hippocampal-dependent place recognition memory accompanied by altered composition of gut microbes. Further analysis revealed that the strongest relationship was detected between hippocampal IL-1b, TLR4, PPARGC1A, PLA24GA, PTGES2, and microbiota PC2 or PC3 (Beilharz et al., 2016), indicating the existence of a gutmicrobiota-hippocampal inflammation-behavior axis. Teasaponin, the major active component of tea, has been shown to attenuate gut microbiota alterations induced by a high-fat diet, prevent recognition memory impairment, and improve neuroinflammation deficits (indicated by levels of TLR4, MyD88, p-JNK, NF-kB, IL-1b, IL-6, and TNF-a) in the hippocampus . Furthermore, treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota, with an increase in the abundance of Actinobacteria and Bacteroidetes; modulated expression of inflammatory genes, such as CD68 mRNA and CD11b mRNA in hippocampal slices; and decreased expression of markers of microglial activation (Distrutti et al., 2014). The Gram-negative facultative anaerobe B. fragilis, which constitutes an appreciable proportion of the human gastrointestinal gut microbiome that secretes an unusually complex mixture of neurotoxins, including extremely proinflammatory lipopolysaccharides (LPS) (Zhao and Lukiw, 2018). Unexpectedly, Zhang et al. reported abundant LPS immunoreactivity in the AD-affected hippocampus, indicating that a major source of proinflammatory signals in the AD brain may originate from the gut microbiome due to intestinal mucosa barrier and blood-brain barrier dysfunction . It has been shown that LPS-induced changes in Firmicutes commensals and depletion Proteobacteria opportunistic organisms were reversed to control levels by FMT in male rats, and LPS mice treated with FMT showed better spatial memory in behavioral tests . A recent study by Mohammadi et al. showed that a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) reversed LPS-induced elevation of both the circulating and hippocampal levels of proinflammatory cytokines, and attenuate the effect of LPS on memory (Mohammadi et al., 2019). Furthermore, LPS were shown to drive an NF-kB-miRNA-mediated deficiency in gene expression that contributes to alterations in synaptic architecture, synaptic deficits, amyloidogenesis, innate immune defects, and progressive inflammatory signaling, all of which are characteristics of AD-type neurodegeneration (Zhao and Lukiw, 2018). Many factors are involved in the pathogenic gut microbiota-related systemic inflammation, due to increased LPS and proinflammatory cytokines, barrier dysfunction, and dysfunctional vago-vagal gut-brain axis (Daulatzai, 2014). The colitis mice showed impaired memory, increased fecal and blood levels of LPS, an increase in Enterobacteriaceae, but a decrease in Lactobacillus johnsonii. These changes in behaviors and LPS production could be induced by treatment with E. coli isolated from the feces of colitis mice accompanied with NF-kB activation and TNF-a expression as well as suppressed BDNF expression in the hippocampus of mice. However, all these changes could be reversed by treatment with Lactobacillus johnsonii (Jang et al., 2018). This was further demonstrated by oral administration of Lactobacillus brevis OW38 to aged mice showing reduced LPS levels in colon fluid and blood and reduced ratio of Firmicutes to Bacteroidetes or Proteobacteria to Bacteroidetes, which was significantly higher in aged mice than in young mice. Treatment with OW38 in aged mice inhibited the expression of inflammatory markers (such as TNF and IL-1b) and NF-kB activation, and suppressed the expression of senescence markers (p16, p53, and SAMHD1) in the hippocampus of aged mice (Jeong et al., 2016). These results strongly demonstrated that gut microbiota disturbance could induce hippocampal inflammation and memory impairment. Moreover, it has been reported that when FMT is conducted, young recipient rats show impairment in cognitive behavior but an increase in expression of proinflammatory AGEs and their receptor, accompanied by changes in gut microbiota composition . Specifically, Lactobacillus plantarum decreased the expression of hippocampal TLR4 (Mohammed et al., 2020).
Taken together, the alterations in the gut microbiota may change the inflammatory status in the hippocampus and hippocampus-dependent behaviors, which could be improved by probiotics, microbiota transplantation, or diet management. These results are summarized in Figure 3 and Table 4.

GUT MICROBIOTA AND HIPPOCAMPAL ALZHEIMER'S DISEASE PATHOLOGIES
Human microbiota may strongly influence the pathology of AD, the deposition of Ab, and formation of neurofibrillary tangles in the hippocampus (Kohler et al., 2016). The effects of aging and the risk of neurodegenerative diseases can be reduced by probiotics, or by combining probiotics and prebiotics known as synbiotics, which can significantly modify the composition of the gut microbiome (Lye et al., 2018). Long-term (6 months) antibiotic treatment of 2-week-old AD mice induced shifts in gut microbial composition and diversity, a decrease in Ab plaque deposition, but an increase in soluble Ab in the brain of AD mice, suggesting that gut microbiota diversity could regulate host innate immunity mechanisms that are related to Ab amyloidosis (Minter et al., 2016). Moreover, early postnatal (days 14-21) antibiotic treatment resulted in long-term alterations in gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduced brain Ab deposition in aged AD mice, accompanied by reduced plaque-localized microglia and astrocytes (Minter et al., 2017). A recent study showed that when 3xTg-AD mice in the early stage of AD were treated with the SLAB51 probiotic formulation, the gut microbiota and their metabolites changed significantly, and the impaired neuronal proteolytic pathways (the ubiquitin proteasome system and autophagy) were partially recovered. Cognitive function improved and the accumulation of Ab aggregates was reduced (Bonfili et al., 2017).  In APP/PS1 mice, quercetin treatment increased gut microbial diversity and relative abundance of Glutamicibacter, Facklamia, and Aerocorrus; it also improved learning and memory in the Morris water maze test. Hippocampal BDNF levels were increased but Ab plaques and p-Tau decreased; further analysis revealed that hippocampal p-Tau at ser396 was negatively correlated with Aerococcus, but p-Tau at ser404 was negatively correlated with Facklamia . Curcumin has also been shown to improve spatial learning and memory abilities and reduce Ab plaque in the hippocampus of APP/PS1 mice. These changes may be related to the altered abundance of Bacteroidaceae, Prevotellaceae, Lactobacillaceae, and Rikenellaceae at the family level, and Prevotella, Bacteroides, and Parabacteroides at the genus level . Additionally, as mentioned above, the administration of TTK extract and Tibetan fermented milk also improved memory loss and reduced the deposition of hippocampal Ab that involved changes in gut Clostridiales, Erysipelotrichales, Desulfovibrionales, Lactobacillales, Bacteroides, Faecalibacterium spp. Mucispirillum, and Ruminiclostridium (Kim et al., 2020;Liu et al., 2020). Additionally, mice treated with a ketogenic diet for 16 weeks showed significantly increased abundance of putatively beneficial gut microbiota (Akkermansia muciniphila and Lactobacillus), and reduced putatively proinflammatory taxa (Desulfovibrio and Turicibacter). These changes facilitated the clearance of Ab, and reduced the risk of AD (Ma et al., 2018). Moreover, oral administration of grape seed polyphenol extract (GSPE) resulted in an increase in two phenolic acids, 3hydroxybenzoic acid and 3-(3-hydroxyphenyl) propionic acid in rats. This treatment also interfered with the assembly of Ab peptides into senile plaques, suggesting an important contribution of the intestinal microbiota to the protective activities of GSPE in AD . In a population-based cross-sectional cohort study, a very intriguing discovery was that the Mediterranean diet, which contains an unusually large quantity of Lactobacilli, seemed very effective in preventing AD (Jin et al., 2018). Furthermore, it has been reported that in APP/PS1mice, prebiotic fructooligosaccharide (FOS) treatment altered microbial composition, ameliorated cognitive deficits and AD pathological changes, and upregulated the expression levels of hippocampal synaptic proteins (Sun et al., 2019). Similar results were also detected in other species. When AD rats were treated with FOS from Morinda officinalis, the learning and memory abilities were significantly ameliorated, accompanied with maintenance of the diversity and stability of the gut microbial community . Interestingly, a recent study revealed that gut microbiota diversity and composition might also mediate the effects of chronic noise exposure on cognitive impairment and hippocampal Ab deposition, and microbiota transplantation demonstrated that the host impairment of epithelial integrity and AD-like changes were driven by the noise exposure-altered microbiota (Cui et al., 2018).
Taken together, as reviewed by , the composition and diversity of gut microbiota may be regulated in many ways, such as antibiotics, probiotics, diet, plant extracts, and microbiota transplantation. These treatments were also shown to be deeply involved in AD pathology, especially the formation and deposition of Ab, and behaviors. These results are summarized in Figure 4 and Table 5.

CLINICAL APPLICATIONS OF PROBIOTICS AND ANTIBIOTIC ON BRAIN COGNITIVE FUNCTION
Limited clinical trials have addressed the effects of probiotics on brain function, including memory, depression, and stress. Steenbergen et al. reported that multispecies probiotic intervention could reduce negative thoughts associated with a sad mood in healthy volunteers (Steenbergen et al., 2015). Later, probiotic administration was shown to alter brain activities CD68, CD11b, microglia activation (Distrutti et al., 2014) LPS and FMT Firmicutes phylum, Proteobacteria phylum spatial memory  LPS and probiotic formulation Lactobacillus helveticus R0052, Bifidobacterium longum R0175)  Ab clearance (Ma et al., 2018) Mediterranean diet Lactobacilli AD -preventing (Jin et al., 2018) grape seed polyphenol extract microbiota metabolism Ab deposit  noise/microbiota transplantation composition and diversity Ab deposit learning and memory (Cui et al., 2018) FOS microbial composition AD pathology, synaptic plasticity cognition (open field, Morris water maze, object recognition) (Sun et al., 2019) FOS diversity and stability learning and memory  related to emotional memory, decision-making tasks, anxiety, negative affect, and worry, which were also accompanied by subtle shifts in the gut microbiome profile (Bagga et al., 2018;Tran et al., 2019). Bifidobacterium longum 1714 ™ also modulated the resting neural activity in several brain regions including the hippocampus, fusiform, and temporal cortex, which correlated with enhanced vitality and reduced mental fatigue in healthy volunteers during social stress . Inoue et al. reported that probiotic bifidobacteria supplementation showed stronger effects on the improvement of mental condition compared to moderate resistance training (Inoue et al., 2018). Probiotics have also been shown to be effective in patients with cognitive disorders. In patients with mild cognitive impairment, treatment with Lactobacillus plantarum C29fermented soybean supplement (DW2009) resulted in significant improvement in cognitive function (Hwang et al., 2019). For major depressive patients, probiotics alone or in combination with antidepressants are effective and well tolerated (Miyaoka et al., 2018;Chahwan et al., 2019). Similarly, probiotic Lactobacillus plantarum 299v decreased kynurenine concentration and improved cognitive functions in patients with major depression (Rudzki et al., 2019). The probiotic Lactobacillus plantarum P8 gender-dependently alleviated stress and enhanced memory and cognition, such as social emotional cognition, and verbal learning and memory (Lew et al., 2019).
In peripheral disorders, probiotics and antibiotics may affect brain function through regulation of microbiota. Probiotic Bifidobacterium Longum NCC3001 administration has also been shown to reduce depression and alter brain activity in patients with irritable bowel syndrome (Pinto-Sanchez et al., 2017), improve impulsivity and decision-making in patients with fibromyalgia (Roman et al., 2018), and neurocognitive functions in human immunodeficiency virus transfected patients (Ceccarelli et al., 2017). Rifaximin is a gut-specific antibiotic. Several clinical trials demonstrated that in patients with minimal hepatic encephalopathy (MHE), rifaximin induced a significant improvement in cognition, including working memory that involved Enterobacteriaceae, Porphyromonadaceae, and Bacteroidaceae, endotoxemia, and several serum fatty acids. This treatment also decreased Veillonellaceae and increased Eubacteriaceae, inducing a shift from pathogenic to beneficial metabolite linkages (Bajaj et al., 2013;Ahluwalia et al., 2014). Additionally, in patients with MHE, oral capsular FMT (enriched in Lachnospiraceae and Ruminococcaceae) improved cognition. Inflammation was positively correlated with greater complexity of beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae; increased duodenal mucosal diversity with higher Ruminococcaceae and Bifidobacteriaceae; and lower Streptococcaceae and Veillonellaceae, indicating the beneficial effects of capsular FMT on inflammation and cognition in patients with cirrhosis (Bajaj et al., 2019a;Bajaj et al., 2019). The above results were summarized in Table 6.

CONCLUSIONS
The gut microbiota is regarded as the second genome of the human body. Its composition and diversity changes frequently under different conditions. The hippocampus is the center for learning and memory, which is closely related to dementia and many other mental disorders. In this manuscript, we reviewed recent findings on the relationship between intestinal microbes and the plasticity, neurochemicals, and function of the hippocampus. We highlighted the advances in modulating hippocampal structure and behavior using probiotics, prebiotics, and diet through the gut microbiota-hippocampus axis, as summarized in Figure 5. Evidence indicates that the gut microbiota is altered in AD. Therefore, modifying the gut microbiota may affect this disease (Agahi et al., 2018). An abundance of "good bacteria" such as Bifidobacterium or their products have generally been believed to be beneficial, while "bad bacteria" such as Clostridium are assumed to be detrimental (Park et al., 2017). Escherichia coli and Salmonella enterica are among the many bacterial strains that express and secrete Ab and contribute to AD pathogenesis (Tse, 2017). Clinical studies have shown that, in cognitively impaired elderly patients with brain amyloidosis, the anti-inflammatory species Eubacterium rectale and Bacteroides fragilis were more abundant, while proinflammatory genera such as Escherichia/Shigella were higher. Supplementation with Lactobacilli-and Bifidobacteria-based probiotics was neuroprotective in AD subjects (Mancuso and Santangelo, 2018). However, the results of current studies are controversial. For example, Vogt et al. reported an increase in the abundance of Bacteroidaceae, Rikenellaceae, and Gemellaceae, but a decrease in that of Ruminococcaceae, Bifidobacteriaceae, Clostridiaceae, Mogibacteriaceae, Turicibacteraceae, and Peptostreptococcaceae in AD patients when compared with the controls (Vogt et al., 2017); Zhuang et al. reported an increase in the abundance of Ruminococcaceae, Enterococcaceae, and Lactobacillaceae, but a decrease in that of Lanchnospiraceae, Bacteroidaceae, and Veillonellaceae compared with the control group (Zhuang et al., 2018).
The exact trigger of AD remains unknown. Current treatments for AD are limited, and great efforts have been made to target Ab plaques, but these attempts have often ended in failure (Reiss et al., 2018;Salminen et al., 2018). Recent progress in the effects of gut microbiota on hippocampus-dependent learning and memory have opened a new window for understanding the onset and progression of AD. Thus, modulation of the gut microbiota has been regarded as a preventive and therapeutic target against this worldwide challenge. However, how the gut microbiota affects the structure and function of the hippocampus is far from clear. It has been shown that bacterial metabolites, such as LPS and Ab, may act through the vagus nerve pathway, the systemic pathway (with the release of hormones, metabolites, and neurotransmitters), and the immune pathway (by the action of cytokines) to increase the permeability of the mucosa-intestinal barrier and blood-brain barrier, induce FIGURE 5 | Schematic illustration shows how gut microbiota affect hippocampal plasticity and behaviors through gut-hippocampus-axis. The composition and diversity, the levels of LPS and Ab, proinflammatory and inflammatory factors, and other metabolites (such as hormones) of gut microbiota could be affected by many treatments (antibiotics, germ free administration, diet, pre-and pro-biotics, and fecal transplantation). The alterations occurred in the gut microbiota affect many aspects of the hippocampus (such as amino acids, expression of specific proteins, AD-related pathologies) through the vagus nerve pathway, the systemic pathway (with the release of hormones, metabolites, cytokines, and neurotransmitters) to increase the permeability of mucosa-intestinal barrier and blood-brain barrier and finally regulate hippocampus-dependent cognition and behaviors. hippocampal inflammation, and ultimately affect hippocampusdependent functions (Bostanciklioglu, 2019;Garcez et al., 2019;Gomez-Eguilaz et al., 2019). All these still require further experimental evidence, and we also lack human observational or interventional data to propose any clinical recommendations.

AUTHOR CONTRIBUTIONS
YY and DC conceived this article. WT and ZM performed the literature search, data analysis, and draft preparation. YY and DC critically revised the manuscript. NL, YL, and LL helped in the data analysis and draft preparation. All authors contributed to the article and approved the submitted version.

FUNDING
This study was supported in part by the National Natural Science Foundation of China (NSFC 81500408 to YY and NSFC 81972305 to DC), Foundation and Frontier Projects of Chongqing Science and Technology Commission (Grant No. cstc2016jcyjA0079 to YY), and China Postdoctoral Science Foundation Grant (2019M653976).